Anellated β-carbolines

ABSTRACT

Compounds of formula I ##STR1## are described, as well as the process for their production and their use in pharmaceutical agents.

This application is a 371 of PCT/DE96/00632 filed Apr. 3, 1996.

The invention relates to anellated β-carbolines, their production anduse in pharmaceutical agents.

It is known from numerous publications that β-carbolines have anaffinity to the benzodiazepine receptors, although they differstructurally from benzodiazepines, and that they are used aspsychopharmaceutical agents because of the affinity to the BDZreceptors. β-Carbolines can have an antagonistic, agonistic or inverselyagonistic effect on the properties that are known of BDZ receptors.

It has now been found that the compounds according to the invention havea very good affinity to the benzodiazepine receptors and have a specificinverse agonistic effect on the properties that are known regardingbenzodiazepines. The compounds have anxiolytic, anti-amnestic andnootropic activities and improve learning and attentiveness. Because oftheir action profile, the compounds according to the invention aresuitable for the production of pharmaceutical agents for treatinggeriatric symptoms, as well as to mitigate cognitive deficits andincrease vigilance, without serious side effects occurring.

The invention relates to the compounds of formula I, their isomers,tautomers and salts ##STR2## in which

R³ means hydrogen, C₁₋₆ alkyl, --CO--R¹, --C≡N, phenyl, which optionallyis substituted one to three times with C₁₋₄ alkyl, C₁₋₄ alkoxy, halogenor --CF₃, ##STR3##

R⁴ means hydrogen, C₁₋₆ alkyl, C₁₋₄ alkoxy-C₁₋₂ alkyl,

A represents a 5- to 6-membered unsaturated ring, in which 1-2 C atomscan be replaced by N, O and/or S and can be substituted with R⁵ and R⁶,and

R⁵ and R⁶ are the same or different and mean hydrogen, C₁₋₆ alkyl, C₁₋₆alkoxy, hydroxy, which can be functionally modified, NR⁷ R⁸, COR, C₁₋₆alkyl, which is substituted with optionally functionally modifiedhydroxy, C₁₋₄ alkoxy or halogens, a C₆₋₁₂ aryl or a 5- to 6-memberedhetaryl radical, which contains one to three N, O and/or S atoms, andthe aryl and hetaryl radical can be substituted with C₁₋₄ alkyl, C₁₋₄alkoxy, halogen or CF₃, or

R⁵ and R⁶ together mean a --(CH₂)_(n) group and

R¹ and R mean hydroxy, C₁₋₆ alkoxy or NR¹⁰ R¹¹,

R² means hydrogen, C₁₋₄ alkyl or C₁₋₄ alkoxy-C₁₋₂ alkyl,

R⁹ means hydrogen or C₁₋₆ alkyl,

n means 3 or 4,

R⁷ and R⁸ each mean hydrogen, C₁₋₆ alkyl, acyl or phenyl, which can besubstituted with C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen or CF₃,

R¹⁰ and R¹¹ each mean hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl or a C₆₋₁₂aryl radical or a 5- to 6-membered hetaryl radical, which contains oneto three N, O and/or S atoms, and the aryl and hetaryl radical can besubstituted with C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen or CF₃.

Alkyl contains respectively both straight-chain and branched-chainradicals, such as, for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl and hexyl.

As aryl radicals R⁵, R⁶, R¹⁰ or R¹¹, there can be mentioned, forexample, phenyl, biphenyl and α- or β-naphthyl, which optionally aresubstituted in 1 to 3 places.

If R⁵, R⁶, R¹⁰ or R¹¹ means a hetaryl radical, six-membered ringheteroaromatic compounds with up to 3 nitrogen atoms and five-memberedring heteroaromatic compounds with one to two oxygen, sulfur and/ornitrogen atoms are meant, such as, for example, triazine, pyridine,pyrimidine, pyrazine, pyridazine, furan, thiophene, pyrrole, imidazole,thiazole, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, which can be substitutedin each case in 1 to 3 places.

Halogen is defined respectively as fluorine, chlorine, bromine andiodine. Cycloalkyl respectively stands for cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl.

Alkyl radical R⁵, R⁶ can be substituted in 1 to 3 places or else bepresent in perhalogenated form.

The hydroxy groups can be functionally modified, for example, byetherification or esterification. As ether and acyl radicals, theradicals that are known to one skilled in the art are considered.Preferred are easily cleavable ether radicals, such as, for example, thetetrahydropyranyl, tetrahydrofuranyl, tert-butyldimethylsilyl,tert-butyldiphenylsilyl, tribenzylsilyl radical. As acyl radicals, forexample, C₁₋₆ alkanoyls such as acetyl, propionyl, butyryl and benzoylare suitable.

If several hydroxy groups are present, cyclic acetals or ketals can bepresent, such as 1,3-dioxane or 1,3-dioxolane radicals, such as2-phenyl-1,3-dioxane, 2,2-dimethyl-1,3-dioxolane, which are produced,for example, by reaction with acetone, an enol ether, 1,1-alkyl dihalideor acetone dimethyl ketal.

Acyl group R⁷ or R⁸ contains aromatic and aliphatic acyl groups such asbenzoyl and benzoyls that are substituted in one to three places, aswell as straight-chain or branched alkanoyls with up to 6 carbon atoms.

If A contains a heteroaromatic five-membered ring, the latter can havethe following groupings: ##STR4##

As heteroaromatic six-membered rings, there can be mentioned, forexample, the following groupings: ##STR5##

Substituents R⁵ and R⁶ can each be in any position on radical A or itstautomeric or isomeric forms. As preferred embodiments of R³, --COR¹ isto be considered, and as preferred embodiments of R¹ and R, hydroxy andC₁₋₆ alkoxy are to be considered.

If a basic function is present, the physiologically compatible salts arederived from inorganic and organic acids. Suitable are inorganic acids,such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acidor organic acids, such as, for example, aliphatic or aromatic mono- ordicarboxylic acids, such as formic acid, acetic acid, maleic acid,fumaric acid, succinic acid, lactic acid, tartaric acid, citric acid,oxalic acid, glyoxylic acid or sulfonic acids, for example, C₁₋₄alkanesulfonic acids, such as methanesulfonic acid or benzenesulfonicacids, optionally substituted by halogen or C₁₋₄, such asp-toluenesulfonic acid.

If an acid function is present, the physiologically compatible salts oforganic bases are suitable as salts, such as, for example, the readilysoluble alkali and alkaline-earth salts, as well as N-methylglucamine,dimethylglucamine, ethylglucamine, lysine, 1,6-hexadiamine,ethanolamine, glucosamine, sarcosine, serinol,tris-hydroxymethylaminomethane, aminopropanediol, Sovak base,1-amino-2,3,4-butanetriol.

The compounds of formula I as well as their salts can be used aspharmaceutical agents because of their affinity to benzodiazepinereceptors. They have different intrinsic action (i.e., agonistic,antagonistic and/or inversely agonistic action) on various isoforms ofthe GABA-benzodiazepine receptor.

To use the compounds according to the invention as pharmaceuticalagents, the latter are brought into the form of a pharmaceuticalpreparation, which, in addition to the active ingredient for enteral orparenteral administration, contains suitable pharmaceutical, organic orinorganic inert vehicles, such as, for example, water, gelatin, gumarabic, lactose, starch, magnesium stearate, talc, vegetable oils,polyalkylene glycols, etc. The pharmaceutical preparations can bepresent in solid form, for example, as tablets, coated tablets,suppositories, capsules, or in liquid form, for example, as solutions,suspensions or emulsions. Moreover, they optionally contain adjuvants,such as preservatives, stabilizers, wetting agents or emulsifiers, saltsfor changing the osmotic pressure or buffers.

For parenteral use, especially injection solutions or suspensions,especially aqueous solutions of active compounds inpolyhydroxyethoxylated castor oil, are suitable.

As vehicle systems, surface-active adjuvants, such as salts of bileacids or animal or plant phospholipids, but also their mixtures as wellas liposomes or their components can be used.

For oral use, especially tablets, coated tablets or capsules with talcand/or hydrocarbon vehicles or binders, such as, for example, lactose,corn or potato starch, are suitable. The use can also take place inliquid form, such as, for example, as juice, to which optionally asweetener is added. The compounds according to the invention areintroduced in a dosage unit of 0.05 to 100 mg of active substance in aphysiologically compatible vehicle.

The dosage of the active ingredients can vary depending on the method ofadministration, age and weight of the patient, type and severity of thedisease to be treated and similar factors. The daily dose is 0.1-300 mg,preferably 0.1-30 mg, whereby the dose can be given as a single dose tobe administered one time or divided into 2 or more daily doses.

The production of the compounds according to the invention is carriedout according to methods that are known in the art. For example,compounds of formula I are attained in that

a) a compound of formula II ##STR6## is reacted with a 2-azadiene offormula III ##STR7## in which R³, R⁴ and A have the above meaning, and Xand Y represent leaving groups, in the presence of acids or

b) a compound of formula IV ##STR8## in which R³, R⁴ and A have theabove meaning, is aromatized or c) a compound of formula V ##STR9## inwhich R³ and R⁴ have the above meaning, is reacted with anα,β-unsaturated aldehyde to a fused pyridine or reacted with a primaryamine H₂ N--CH₂ --R⁵ to a fused imidazole or the diazonium salts thatare obtained with nitrites are reacted with acetoacetic acid derivativesto an ethylidenehydrazine derivative and the latter is cyclized topyrrole or reacted with thiocyanate or isothiocyanate derivatives to afused thiazole or

d) a compound of formula VI ##STR10## in which R³ and R⁴ have the abovemeaning, is reacted with a primary amine H₂ N--CH₂ --R⁵ to a fusedoxazole or with a vicinal primary diamine ##STR11## to a fused pyrazineor e) a nitrile oxide of formula VII ##STR12## is cyclized with anacetylene derivative ≡----R² to an isoxazole derivative,

f) an α-haloketone of formula VIII ##STR13## in which R⁴ and A have theabove meaning and Z is halogen, is reacted with a thioamide H₂ N--CS--R⁹to a compound with R³ meaning thiazolyl or

g) a nitrile of formula IX ##STR14## in which R⁴ and A have the abovemeaning, is cyclized with an azide to a compound with R³ meaningtetrazolyl and optionally then an ester group is saponified orreesterified, a carboxyl group is esterified, an amino group isalkylated or acylated, a functionally modified hydroxy group isreleased, the isomers are separated or the physiologically compatiblesalts are formed.

The reaction according to the invention of compounds of formula II with2-azadienes of formula III to the compounds of formula I according toprocess a) is carried out according to EP-A-110813 in the presence ofacids at temperatures of 0 to 150° C. Leaving groups X and Y can be thesame or different; especially suitable are C₁₋₃ dialkylamines, such asdimethylamine, diethylamine and diisopropylamine, and cyclic amines,such as pyrrolidine.

The reaction is performed, for example, so that the indole derivativeand the azadiene first is stirred at room temperature in an organicacid, such as, for example, formic acid, acetic acid, propionic acid ortrifluoroacetic acid, and then is heated up to boiling temperature ofthe reaction mixture.

The acid can be used simultaneously as reactant and as solvent. Solventssuch as, for example, alcohols, ethers, ketones, esters, such as ethylacetate, hydrocarbons, such as toluene, or halogenated hydrocarbons,such as carbon tetrachloride, however, can also be added.

The amount of acid can be varied within wide limits, but it is used inexcess. Preferably, a 3 to 10-fold acid excess, relative to theazadiene, is selected.

The molar ratios of indole and azadiene are not critical for the successof the reaction. In general, approximately equal molar amounts of thereactants are used, whereby quantitative ratios of 1 mol of aniline and1-3 mol of azadiene are preferred. The reaction according to theinvention can basically also be performed in the above-indicatedsolvents with catalytic amounts of mineral acids, such as sulfuric acid,hydrochloric acid, perchloric acid or organic acids, such asp-toluenesulfonic acid and trifluoroacetic acid.

To aromatize the compounds of formula IV, the processes that are knownregarding the β-carbolines are suitable, such as, for example, thedehydrogenation with tert-butyl hypochlorite (EP-A- 190 987) or withtrichloroisocyanuric acid (WO 94/12 498).

The fusing of unsaturated ring A according to process variants c) and d)is carried out as a function of the position of the amino or hydroxygroup in 5,6- or 6,7-position of the β-carboline, preferably in5,6-position. Optionally accumulating isomer mixtures are separated inthe usual way by fractionated crystallization or chromatography.

If a pyridine ring is synthesized, this can be carried out according tothe synthesis of Skraup [G. Alunni-Bistocchi et al. J. Chem. Soc. PerkinTrans. 1, 2935 (1992)], by, for example, an α,β-unsaturated aldehyde,which can be produced intermediately, being added to the amine and thenbeing cyclized under the influence of acids and aromatized with anoxidizing agent, such as arsenopentoxide, iron(III) oxide or picricacid. The reaction is performed at temperatures from room temperature to150° C. in inert solvents, such as toluene, xylene.

To produce an imidazole, for example, the correspondingamino-β-carboline derivative is condensed with a primary amine R⁵ --CH₂--NH₂ in the presence of an oxidizing agent, such as MnO₂, at roomtemperature or elevated temperature in inert solvents, such asdichloromethane, dichloroethane or ethylene glycol dimethyl ether.

The pyrrolocarboline can be produced from, e.g., the ethylenehydrazino-β-carboline derivative, by the latter being heated in an inertsolvent, such as hydrocarbons, e.g., toluene, xylene, benzene, in thepresence of organic or inorganic acids or polyphosphoric acid esters.

The production of the ethylene hydrazino starting compounds can becarried out with the aid of the Sandmeyer reaction, by, e.g., thediazonium salts formed intermediately from the amino compounds withnitrites being reacted with alkali salts of the acetoacetic acid estersin protic solvents, such as water or alcohols, at temperatures of 0° C.up to room temperature.

Thiazolo-carbolines can be produced, for example, by reaction of thecompounds of formula V with thiocyanate or isothiocyanate compounds. Thereaction is carried out suitably in an inert solvent in the presence ofan organic or inorganic acid, whereby if an organic acid is used, thelatter can be used as solvent. For cyclization, in general an oxidizingagent, such as, for example, bromine, is added. Starting fromhydroxy-β-carbolines, oxazolocarbolines are obtained analogously to theScraup synthesis that is described above by reacting a primary amine inthe presence of an oxidizing agent such as MnO₂ at room temperature orelevated temperature in an inert solvent. If a vicinal primary diaminocompound is used in the reaction instead of a primary amine, thecorresponding pyrazine derivatives, whose isomer mixtures can beseparated in the usual way such as chromatographically or byfractionated crystallization, are obtained.

The reaction of the nitrile oxides of formula VII with the acetylenederivatives can be carried out, for example, according to the methodsthat are described by K. G. B. Torsell (K. G. B. Torsell, NitrileOxides, Nitrones and Nitronates in Organic Synthesis, 1988 VCHVerlagsgesellschaft mbH). In this connection, generally first thenitrile oxide is produced, which then is reacted with an acetylenederivative without isolation.

The molar ratios of nitrile oxide and acetylene can vary within limits.In general, approximately equal molar amounts of the reactants are used,but it can often also be advantageous to use more of the acetylenederivative. The reaction is performed in an aprotic solvent attemperatures of -78° C. to 150° C., preferably -20° C. to 50° C.

As solvents, for example, aliphatic and cyclic ethers, such as diethylether, tetrahydrofuran, dioxane, halogenated hydrocarbons, such asdichloroethane, methylene chloride, chloroform, hydrocarbons, such ashexane, pentane and dimethylformamide, dimethyl sulfoxide, are suitable.

If the starting compounds are gaseous, such as, for example, acetylene,it is advantageous to use in the reaction the corresponding liquidcompounds, which have a then easily cleavable group. As an easilycleavable group, for example, the trialkylsilyl group is suitable. Thecleavage is carried out before the working-up of the reaction mixtureaccording to the known methods, such as, for example, by adding bases atroom temperature. Suitable bases are, for example, alkali hydroxides andalkali alcoholates, such as sodium or potassium hydroxide, methylate orethylate, or fluorides, such as cesium fluoride or tetra-n-butylammoniumfluoride.

B-carboline derivatives protected in 9-position optionally can be usedin the reaction. The protective group is to be cleaved in the usual wayin the working-up of the reaction mixture or subsequently by treatmentwith bases or acids depending on the type of protective group.

The production of the nitrile oxides is carried out, for example, byreacting β-carboline-3-carbaldehydes to the corresponding oximes, whichcan be converted to hydroxamic acid halides, for example, withN-halosuccinimide, tert-butoxychlorite or Na-halosuccinimide,tert-butoxychlorite, or Na-hypochlorite in aprotic solvents. With basessuch as Na- or K-alcoholates, trialkylamines, Hunig base, DBU ordiazabicyclooctane, hydrogen halide is cleaved from the hydroxamic acidhalides, and nitrile oxides, which are discarded without isolation orcycloaddition, are obtained (R. Annunziata et al., J. Chem. Soc. 1987,529).

The production of the β-carboline-3-carbaldehydes can be carried out,for example, according to the process that is described in EP-305 322from the β-carboline-3-carboxylic acid alkyl esters.

The reaction with α-haloketones according to process f) is carried outaccording to the methods that are described in The Chemistry ofHeterocyclic Compounds Vol. 34 Part 1, page 180 ff (1979). For example,the thioamide in solution or in suspension is reacted with theα-haloketone, especially the chloroketone or bromoketone, attemperatures up to the boiling temperature of the reaction mixture. Asinert solvents, alcohols, cyclic and acyclic ethers, esters,hydrocarbons and halogenated hydrocarbons are suitable.

The production of the 3-tetrazolyl-β-carbolines can be carried out, forexample, according to the process with HN₃ that is described inEP-A-54507 or according to the methods that are described in E. W.Thomas, Synthesis (1993), page 767, P. Ornstein et al. J. Med. Chem. 362046, (1993).

The hydrolysis of an ester group can be carried out in an acid oralkaline manner in the usual way, for example, with aqueous alkali oralkaline-earth solutions, optionally by adding organic solvents, such asalcohols, at temperatures from room temperature to 150° C. or accordingto the processes that are described in EP-A-161 574.

If a re-esterification is desired, the methods that are described inEP-A-237 467 can be used, by the re-esterification taking place withalkali alcoholates or the corresponding alcohol, optionally by addingtitanium-tetraisopropylate as catalyst at elevated temperature. Theintroduction of the tert-butyl ester group is carried out by, e.g.,reaction of carboxylic acid with tert-butoxy-bis-dimethyl-aminomethane.

The esterification of the carboxylic acid takes place in a way known inthe art, for example, with the corresponding alcohol in acid or in thepresence of an activated acid derivative. As activated acid derivatives,for example, acid chloride, acid imidazolide or acid anhydride aresuitable.

If an alkylation of the amino group is desired, alkylation can beperformed according to usual methods, for example, with alkyl halides.The acylation of the amino group is carried out according to the knownmethods. For example, it is reacted in an aqueous medium in the presenceof a base with the corresponding acid anhydrides or acid halides.

The release of the functionally modified hydroxy group is carried outaccording to the methods that are known to one skilled in the art. Forexample, the cleavage of ether protective groups is performed in anaqueous solution of an organic acid, such as, for example, formic acid,acetic acid, propionic acid, trifluoroacetic acid, citric acids, i.a.,or in an aqueous solution of an inorganic acid, such as, for example,hydrochloric acid, or by using Lewis acids, such as boron trifluorideetherate.

Silyl protective groups can be removed, for example, with fluorides,such as tetrabutylammonium fluoride or cesium fluoride.

The saponification of acyl groups is performed according to the methodsthat are known to one skilled in the art, such as, for example, withbasic catalysts, such as, for example, with alkali or alkaline-earthcarbonates or -hydroxides in an alcohol or the aqueous solution of analcohol.

The compounds of formula I can be isolated from the reaction mixture andpurified in a way known in the art. Acid addition salts can be convertedinto the free bases in the usual way, and the latter optionally in aknown way into physiologically compatible acid addition salts, forexample, by the solution being mixed with a concentrated solution of thedesired acid.

If the compounds of formula I contain a chiral center, the opticallyactive compounds can be obtained starting from optically active startingcompounds or from the racemates in a way known in the art. Theseparation of enantiomers can be carried out by, for example,chromatography on optically active vehicles, by reaction with opticallyactive acids and subsequently fractionated crystallization.

For the formation of physiologically compatible acid addition salts, acompound of formula I is dissolved, for example, in a little alcohol andmixed with a concentrated solution of the desired acid.

In so far as the production of the starting compounds is not described,the latter are known or can be produced analogously to known compoundsor the processes that are described here.

For example, the production of 3-carboxylic acid esters of formula VI isdescribed in EP-A-130 140, and the production of compounds of formula Vis described in EP-A-54 507.

The affinity to the benzodiazepine receptors is determined by studyingthe ability of test substances to displace radiolabeled benzodiazepinesfrom a benzodiazepine receptor. To study the anxiolytic effect, thecompounds are tested in the 4-plate test according to the method ofBoissier et al. Eur. J. Pharmacol. 4, 145-150 (1968).

The antiamnestic action can be tested (DMTP test) according to themethod of B. J. Cole et al. Psychopharmacology (1993) 111:465-471, andattentiveness can be tested according to the method of J. L. Muir et al.Exp. Brain Res (1982) 89:611-622 (9-hole box).

Thus, for example,isopropyl-11-methoxymethyl-3-methyl-pyrazino[2,3-g]-β-carboline-10-carboxylatein "Behavioural Tests of Learning and Memory" (e.g., according to Coleet al., 1994, Psychopharmacol. 116, 135-142) in rats at doses of 10mg/kg i.p. shows an improvement in cognitive performance.

The following examples are to explain the process according to theinvention:

EXAMPLE 1

Isopropyl-11-ethyl-3-methyl-pyrazino[2,3-g]-β-carboline-10-carboline andisopropyl-11-ethyl-2-methyl-pyrazino[2,3-g]-β-carboline-10-carboxylate

20 g of isopropyl-4-ethyl-6-hydroxy-β-carboline-3-carboxylate isdissolved in 800 ml of ethylene glycol dimethyl ether (DME) and 7.2 mlof 1,2-diaminopropane while nitrogen is introduced at room temperature.While being stirred, 175 g of manganese(IV) oxide is introduced inportions into the solution within 30 minutes, so that the reactiontemperature does not rise above 28° C. After the addition ofmanganese(IV) oxide is completed, another 2.9 ml of 1,2-diaminopropaneis added. The reaction mixture is stirred under nitrogen atmosphereovernight. The reaction mixture is filtered on diatomaceous earth, andthe filter residue is rewashed five times with 100 ml of DME each. Thecombined filtrates are evaporated almost to dryness, and theprecipitated crystals are isolated. The crude crystallizate obtained isrecrystallized three times from methanol.

9.5 g ofisopropyl-11-ethyl-3-methyl-pyrazino[2,3-g]-β-carboline-10-carboxylatewith a melting point of 236.5-237.5° C. is obtained.

The combined mother liquors are evaporated to dryness and then boiledout with isopropyl acetate. The undissolved residue is filtered off andrecrystallized four times from methanol.

265 mg ofisopropyl-11-ethyl-2-methyl-pyrazino[2,3-g]-β-carboline-10-carboxylatewith a melting point of 215-216° C. is obtained.

Analogously, there are produced:

Isopropyl-11-methoxymethyl-3-ethyl-pyrazino[2,3-g]-β-carboline-10-carboxylatemelting point 202-203° C.

isopropyl-11-methyl-3-ethyl-pyrazino[2,3-g]-β-carboline-10-carboxylatemelting point 204-206° C.

isopropyl-3,11-diethyl-pyrazino[2,3-g]-β-carboline-10-carboxylatemelting point 188-190° C.

isopropyl-11-methoxymethyl-pyrazino[2,3-g]-β-carboline-10-carboxylatemelting point 238° C. (decomposition)

isopropyl-11-methoxymethyl-2,3,4,5-tetrahydroquinoxalino-[2,3-g]-β-carboline-12-carboxylatemelting point 224-225° C. (decomposition)

isopropyl-11-methoxymethyl-3-phenyl-pyrazino[2,3-g]-carboline-10-carboxylatemelting point 262-263° C.

isopropyl-11-ethyl-3-phenyl-pyrazino[2,3-g]-β-carboline-10-carboxylatemelting point 235-236° C.

isopropyl-11-methoxymethyl-pyrazino[2,3-g]-β-carboline-10-carboxylatemelting point 195-197° C.

isopropyl-2,11-dimethyl-pyrazino[2,3-g]-β-carboline-10-carboxylatemelting point 155-160° C.

isopropyl-11-methoxymethyl-2,3-dimethyl-pyrazino[2,3-g)-β-carboline-10-carboxylatemelting point 244-245° C.

isopropyl-11-ethyl-2,3-dimethyl-pyrazino[2,3-g]-β-carboline-10-carboxylatemelting point 233-236° C.

isopropyl-11-methyl-2,3-dimethyl-pyrazino[2,3-g]-β-carboline-10-carboxylatemelting point 305° C. (decomposition)

isopropyl-11-methoxymethyl-3-propyl-pyrazino[2,3-g]-β-carboline-10-carboxylatemelting point 172-173° C.

isopropyl-11-ethyl-3-propyl-pyrazino[2,3-g]-β-carboline-10-carboxylatemelting point 184-186° C.

isopropyl-11-ethyl-3-methoxymethyl-pyrazino[2,3-g]-β-carboline-10-carboxylatemelting point 198-199° C.

isopropyl-3,11-bis(methoxymethyl)-pyrazino[2,3-g]-β-carboline-10-carboxylatemelting point 193-194° C.

EXAMPLE 2

7H-Benzo[e]pyrido[3,4]-indole-10-carboxylic acid ethyl ester

Analogously to the process in Example 1 of EP-110 813, the titlecompound with a melting point of 278-280° C. is obtained from3H-benz[e]indole and3-dimethylamino-2-(dimethylaminomethyleneamino-acrylic acid ethyl ester(azadiene 1).

EXAMPLE 3

7H-Benzo[e]pyrido[3,4-b]-indole-11-methoxymethyl-10-carboxylicacid-isopropyl ester

a) Analogously to the process in Example 19 of EP-A-54 507, the7H-benzo[e]pyrido[3,4-b]-indole-11-methoxymethyl-10-carboxylic acidethyl ester with a melting point of 195-197° C. is obtained from3H-benz[e]indole.

b) By re-esterification with titanium(IV) isopropylate, the titlecompound with a melting point of 163-164° C. is obtained from the ethylester.

EXAMPLE 4

7H-Benzo[e]pyrido[3,4-b]-indole-1]-methyl-10-carboxylic acid isopropylester

a) Analogously to the process in Example 60 of EP-A-54 507, the7H-benzo[e]pyrido[3,4-b]-indole-11-methyl-10-carboxylic acid ethyl esterwith a melting point of 244-246° C. is obtained from 3H-benz[e]indole.

b) By re-esterification with titanium(IV) isopropylate, the titlecompound with a melting point of 171-173° C. is obtained from the ethylester.

EXAMPLE 5

7H-Benzo[e]pyrido[3,4-b]-indole-11-ethyl-10-carboxylic acid isopropylester

a) Analogously to the process in Example 60 of EP-A-54 507, the7H-benzo[e]pyrido[3,4-b]indole-11-ethyl-10-carboxylic acid ethyl esterwith a melting point of 201-205° C. is obtained from 3H-benz[e]indole.

b) By re-esterification with titanium(IV) isopropylate, the titlecompound with a melting point of 193-196° C. is obtained from the ethylester.

EXAMPLE 6

10-Methyl-2-propyl-oxazolo[4,5-g]-β-carboline-9-carboxylic acidisopropyl ester

A solution of 570 mg of 6-hydroxy-4-methyl-β-carboline-3-carboxylic acidisopropyl ester in 15 ml of ethylene glycol dimethyl ether is mixed with1 ml of n-butylamine and 5.2 g of manganese dioxide, and it is stirredovernight at room temperature. The reaction mixture is filtered onCelite. After the organic phase is concentrated by evaporation, theremaining residue is chromatographed on silica gel with ethyl acetate.The desired fractions are concentrated by evaporation and absorptivelyprecipitated with ether.

325 mg of 10-methyl-2-propyl-oxazolo[4,5-g]-β-carboline-9-carboxylicacid isopropyl ester with a melting point of 223-224° C. is obtained.

Analogously, there are produced:

10-Ethyl-2-isopropyl-oxazolo[4,5-g]-β-carboline-9-carboxylic acidisopropyl ester melting point 205-207° C.

10-ethyl-2-propyl-oxazolo[4,5-g]-β-carboline-9-carboxylic acid isopropylester melting point 163-165° C.

10-methyl-2-isopropyl-oxazolo[4,5-g]-β-carboline-9-carboxylic acidisopropyl ester melting point 248-249° C.

10-methoxymethyl-2-ethyl-oxazolo[4,5-g]-β-carboline-9-carboxylic acidisopropyl ester melting point 188-189° C.

10-methoxymethyl-2-methyl-oxazolo[4,5-g]-β-carboline-9-carboxylic acidisopropyl ester melting point 191-193° C.

10-methoxymethyl-2-pentyl-oxazolo[4,5-g]-β-carboline-9-carboxylic acidisopropyl ester melting point 188-190° C.

10-methoxymethyl-2-isopropyl-oxazolo[4,5-g]-β-carboline-9-carboxylicacid isopropyl ester melting point 174-176° C.

10-methoxymethyl-2-phenyl-oxazolo[4,5-g]-β-carboline-9-carboxylic acidisopropyl ester melting point 274-276° C.

10-methoxymethyl-2-propyl-oxazolo[4,5-g]-β-carboline-9-carboxylic acidisopropyl ester melting point 188-189° C.

10-methoxymethyl-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-oxazolo[4,5-g]-β-carboline-9-carboxylicacid isopropyl ester melting point 202-203° C.

2-(2,2-dimethyl-1,3-dioxolan-4-yl)-10-methyl-oxazolo[4,5-g]-β-carboline-9-carboxylicacid isopropyl ester melting point 278-280° C.

2-(2,2-dimethyl-1,3-dioxolan-4-yl)-10-ethyl-oxazolo-[4,5-g]-β-carboline-9-carboxylicacid isopropyl ester melting point 228-230° C.

EXAMPLE 7

2-(1,2-Dihydroxvethyl)-10-methoxymethyl-oxazolo-[4,5-g]-β-carboline-9-carboxylicacid isopropyl ester

A solution of 200 mg of2-(2,2-dimethyl-1,3-dioxolan-4-yl)-10-methoxymethyl-oxazolo-[4,5-g]-β-carboline-9-carboxylicacid isopropyl ester in 20 ml of methylene chloride is mixed drop bydrop at room temperature with 1 ml of trifluoroacetic acid, and it isstirred at room temperature under protective gas for another 4 hours.The reaction solution is neutralized with the equimolar amount of sodiumbicarbonate solution. The precipitated solid product is suctioned offand washed with methylene chloride. After the drying in a vacuum at 50°C., 112 mg of2-(1,2-dihydroxyethyl)-10-methoxymethyl-oxazolo-[4,5-g]-β-carboline-9-carboxylicacid isopropyl ester with a melting point of 168° C. (decomposition) isobtained.

Analogously, there are produced:

2-(1,2-Dihydroxyethyl)-10-methyl-oxazolo-[4,5-g]-β-carboline-9-carboxylicacid isopropyl ester melting point 195-196° C. (decomposition)

2-(1,2-dihydroxylethyl)-10-ethyl-oxazolo-[4,5-g]-β-carboline-9-carboxylicacid isopropyl ester melting point 184-186° C. (decomposition)

EXAMPLE 8

10-Methoxymethyl-2-isopropyl-oxazolo-[4,5-g]-9-(5-methoxymethyl-3-isoxazolyl)-β-carboline

10-Methoxymethyl-2-isopropyl-oxazolo[4,5-g]6-tosyl-β-carboline-3-carbaldehydoximehydrochloride in 6 ml of absolute tetrahydrofuran is added in drops to1.4 ml of sodium hypochloride solution at room temperature underprotective gas. It is stirred until the oxime has disappeared (TLCcontrol) for 1 hour at room temperature, then 210 mg of methyl propargylether is added in drops and stirred overnight. After the solvent isdistilled off, it is dispersed in ethyl acetate/water, and the organicphase is dried, filtered and concentrated by evaporation. The residue isdissolved in 8 ml of methanol, mixed with 60 mg of sodium methylate andrefluxed for 1 hour. After the organic phase is concentrated byevaporation, the residue is chromatographed on silica gel and toluene:ethyl acetate=1:1. The desired fractions are concentrated by evaporationand crystallized from ethyl acetate. 81 mg of10-methoxymethyl-2-isopropyl-oxazolo[4,5-g]-9-(5-methoxymethyl-3-isoxazolyl)-β-carbolinewith a melting point of 121-122° C. is obtained.

The carbaldehydoxime hydrochloride required as starting material isproduced according to the process that is described in patent EP 0305322.

Analogously, there is produced:

10-Methoxymethyl-2-isopropyl-oxazolo[4,5-g]-9-(5-methyl-3-isoxazolyl)-.beta.-carbolinemelting point 252-255° C.

EXAMPLE 9

2-Amino-10-ethyl-thiazolo[4,5-g]-β-carboline-9-carboxylic acid isopropylester

297 mg of 6-amino-4-ethyl-β-carboline-3-carboxylic acid isopropyl esteris dissolved in 5 ml of acetic acid, mixed with 152 mg of ammoniumthiocyanate and stirred for 1 hour at room temperature. Then, thereaction solution is cooled to 10° C. and mixed drop by drop with 0.05ml of acetic bromine solution (0.5 ml of BR₂ in 9.5 ml of acetic acid).It is stirred for 1 more hour at 10° C. and then heated to roomtemperature. The reaction mixture is taken up in ethyl acetate/water andneutralized with 10% K₂ CO₃ solution. The organic phase is separated,dried and evaporated to dryness. The residue is triturated with ether.214 mg of the title compound with a melting point of 160° C.(decomposition) is obtained.

EXAMPLE 10

2-Amino-10-methoxymethyl-thiazolo[4,5-g]-β-carboline-9-carboxylic acidisopropyl ester

According to the process that is described in Example 9, the titlecompound with a melting point of 188-192° C. (decomposition) is obtainedfrom 6-amino-4-methoxymethyl-β-carboline-3-carboxylic acid isopropylester.

EXAMPLE 11

2-Acetamido-10-ethyl-thiazolo[4,5-g]-β-carboline-9-carboxylic acidisopropyl ester

100 mg of 2-amino-10-ethyl-thiazolo[4,5-g]-β-carboline-9-carboxylic acidisopropyl ester is suspended in 10 ml of acetic anhydride and heated for15 minutes to 80° C. After cooling, the settled precipitate is filteredoff and recrystallized from ethyl acetate. 51 mg of2-acetamido-10-ethyl-thiazolo[4,5-g]-β-carboline-9-carboxylic acidisopropyl ester with a melting point of 208-210° C. is obtained.

EXAMPLE 12

2-Ethylamino-10-ethyl-thiazolo[4,5-g]-β-carboline-9-carboxylic acidisopropyl ester

a) 297 mg of 6-amino-4-ethyl-β-carboline-3-carboxylic acid isopropylester and 88 mg of methyl isothiocyanate are refluxed for 2 hours in 20ml of isopropanol. The solvent is distilled off in a vacuum, and theresidue is recrystallized from ethyl acetate/ether. 257 mg of4-ethyl-6-(3-ethyl-thioureido)-β-carboline-3-carboxylic acid-isopropylester with a melting point of 234-236° C. is obtained.

b) 0.035 ml of bromine is added in drops at room temperature to asuspension of 180 mg of4-ethyl-6-(3-ethyl-thioureido)-β-carboline-3-carboxylic acid isopropylester in 20 ml of chloroform and then refluxed for 3 hours. The reactionsolution is concentrated by evaporation and taken up in ethyl acetateand 20% aqueous K₂ CO₃ solution. The organic phase is separated, driedand concentrated by evaporation. The residue is recrystallized fromethyl acetate. 141 mg of the title compound with a melting point of275-276° C. is obtained.

EXAMPLE 13

Analogously to the process that is described in Example 11, there areproduced:

2-Methylamino-10-ethyl-thiazolo[4,5-g]-β-carboline-9-carboxylic acidisopropyl ester melting point 200° C. (decomposition)

2-methylamino-10-methyl-thiazolo[4,5-g]-β-carboline-9-carboxylic acidisopropyl ester

2-methylamino-10-methoxymethyl-thiazolo[4,5-g]-β-carboline-9-carboxylicacid isopropyl ester

EXAMPLE 14

Pyrrolo[4,5-g]-β-carboline-2,5-dicarboxylic acid diethyl ester

a) 710 mg of 6-amino-β-carboline-3-carboxylic acid ethyl ester is mixedin 18 ml of water at 4° C. with 1.2 ml of concentrated hydrochloricacid. A solution of 210 mg of sodium nitrite in 20 ml of water is addedin drops to the precipitated salt, and it is stirred for another 15minutes at 4° C. This solution is added in drops at 4° C. to 410 mg ofethyl-2-methylacetoacetate and 1 ml of 50% KOH in 3 ml of ethanol and 6ml of water, and it is stirred for another 3 hours. The reaction mixtureis mixed with 50 ml of water and extracted with ethyl acetate. Theorganic phases are washed with water, dried, and concentrated byevaporation. 250 mg of6-(1-ethoxy-carbonyl-ethylidenehydrazino)-β-carboline-3-carboxylic acidethyl ester is obtained, which is processed without furtherpurification.

b) 750 mg of6-(1-ethoxycarbonylethylidenehydrazino)-β-carboline-3-carboxylic acidethyl ester is refluxed with 1.83 g of polyphosphoric acid ethyl esterin 35 ml of absolute xylene under protective gas for 2 hours. Aftercooling, the xylene is decanted, and the residue is taken up in ethylacetate, filtered on Celite and concentrated by evaporation. The residueobtained is chromatographed on silica gel with ethanol. The desiredfractions are concentrated by evaporation and recrystallized fromethanol. 45 mg of the title compound with a melting point of 198-201° C.is obtained.

EXAMPLE 15

2-Isopropyl-10-methoxvmethyl-1H-imidazo[4,5-g]-β-carboline-9-carboxylicacid isopropyl ester

627 mg of 6-amino-4-methoxymethyl-β-carboline-3-carboxylic acidisopropyl ester is stirred in 10 ml of ethylene glycol dimethyl etherwith 1.6 g of manganese dioxide and 0.98 ml of isobutylamine for 16hours at room temperature. The reaction mixture is filtered on Celite,the filtrate is concentrated by evaporation and chromatographed onsilica gel with methylene chloride and ethanol=10+1. 499 mg of2-isopropyl-10-methoxymethyl-1H-imidazo[4,5-g]-β-carboline-9-carboxylicacid isopropyl ester (oily) is obtained from the desired fractions.

Analogously, there are produced:

2-Isopropyl-10-methyl-1H-imidazo[4,5-g]-β-carboline-9-carboxylic acidisopropyl ester

2-isopropyl-10-ethyl-1H-imidazo[4,5-g]-β-carboline-9-carboxylic acidisopropyl ester

2-phenyl-10-methoxymethyl-1H-imidazo[4,5-g]-β-carboline-9-carboxylicacid isopropyl ester

2-butyl-10-methoxymethyl-1H-imidazo[4,5-g]-β-carboline-9-carboxylic acidisopropyl ester

2-(2,2-dimethyl-1,3-dioxolan-4-yl)-10-ethyl-1H-imidazo[4,5-g]-β-carboline-9-carboxylicacid isopropyl ester

2-(2,2-dimethyl-1,3-dioxolan-4-yl)-10-methoxymethyl-1H-imidazo[4,5-g]-.beta.-carboline-9-carboxylicacid isopropyl ester

2-ethyl-10-methoxymethyl-1H-imidazo[4,5-g]-β-carboline-9-carboxylic acidisopropyl ester

10-methoxymethyl-2-trifluoromethyl-1H-imidazo[4,5-g]-β-carboline-9-carboxylicacid isopropyl ester

10-methoxymethyl-2-(2-thienyl)-1H-imidazo[4,5-g]-β-carboline-9-carboxylicacid isopropyl ester

2-(2-furyl)-10-methoxymethyl-1H-imidazo[4,5-g]-β-carboline-9-carboxylicacid isopropyl ester

2-(4-chlorophenyl)-10-methoxymethyl-1H-imidazo[4,5-g]-β-carboline-9-carboxylicacid isopropyl ester melting point 270° C. (decomposition)

2-(2-chlorophenyl)-10-methoxymethyl-1H-imidazo[4,5-g]-β-carboline-9-carboxylicacid isopropyl ester melting point 205-207° C.

2-(4-methylphenyl)-10-methoxymethyl-1H-imidazo[4,5-g]-β-carboline-9-carboxylicacid isopropyl ester melting point 168° C. (decomposition)

2-(4-methoxyphenyl)-10-methoxymethyl-1H-imidazo[4,5-g]-β-carboline-9-carboxylicacid isopropyl ester melting point 258-260° C.

2-(2-methoxyphenyl)-10-methoxymethyl-1H-imidazo[4,5-g]-β-carboline-9-carboxylicacid isopropyl ester melting point 225-228° C.

EXAMPLE 16

Analogously to the process that is described in Example 7, there areproduced:

2-(1,2-Dihydroxyethyl)-10-methoxymethyl-1H-imidazo[4,5-g]-β-carboline-9-carboxylicacid isopropyl ester melting point 198° C.

2-(1,2-dihydroxyethyl)-10-ethyl-1H-imidazo[4,5-g]-β-carboline-9-carboxylicacid isopropyl ester melting point 168° C.

EXAMPLE 17

10-Ethyl-2-methyl-thiazolo[5,4-g]-β-carboline-9-carboxylic acidisopropyl ester

a) 2500 mg of 6-amino-4-ethyl-β-carboline-3-carboxylic acid isopropylester is dissolved in 40 ml of pyridine, mixed with 0.79 ml of aceticanhydride and heated for 2 hours to 50° C. After 20 ml of water isadded, it is concentrated by evaporation in a vacuum. The residue isdissolved in ethyl acetate and washed with water. The organic phase isseparated, dried and evaporated to dryness. The residue, 3110 mg of6-acetylamino-4-ethyl-β-carboline-3-carboxylic acid isopropyl ester, isprocessed without further purification.

b) 2741 mg of 6-acetylamino-4-ethyl-β-carboline-3-carboxylic acidisopropyl ester is heated to 70° C. in 110 ml of dioxane with 3915 mg ofLawesson's reagent while being stirred. After cooling, it is mixed with100 ml of ethyl acetate and washed with saturated sodium chloridesolution. The organic phases are dried and concentrated by evaporationin a vacuum. The residue is chromatographed on silica gel withtoluene+methanol=8+2. 1541 mg of4-ethyl-6-thioacetylamino-β-carboline-3-carboxylic acid isopropyl esterwith a melting point of 158-160° C. is obtained from the desiredfractions.

c) 450 mg of K₃ Fe(CN)₆ is dissolved in 1.8 ml of water, mixed with 1.4ml of 1N NaOH and cooled to 4° C. 200 mg of4-ethyl-6-thioacetylamino-β-carboline-3-carboxylic acid isopropyl esterin 4 ml of pyridine is added in drops to this solution and stirred foranother 2 hours at this temperature. The reaction mixture is taken up inethyl acetate, washed with water, dried and concentrated by evaporation.The residue is chromatographed on silica gel with toluene+ethanol=95+5.The desired fractions are concentrated by evaporation and stirred upwith ether. 30 mg of the title compound with a melting point of 239-240°C. is obtained.

What is claimed is:
 1. A compound of the formulae I, or an isomer, tautomer or salt thereof ##STR15## in which R³ means hydrogen, C₁₋₆ alkyl, --CO--R¹, --C≡N, phenyl which optionally is substituted one to three times with C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen or --CF₃, ##STR16## R⁴ means hydrogen, C₁₋₆ alkyl, or C₁₋₄ alkoxy-C₁₋₂ alkyl, provided that R³ and R⁴ are not simultaneously hydrogen, andA represents a 5- to 6-membered unsaturated ring, in which 1-2 C atoms are optionally replaced by N, O and/or S and which is optionally substituted by R⁵ and R⁶, where R⁵ and R⁶ are the same or different and mean hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy which is optionally functionally modified, NR⁷ R⁸, COR, C₁₋₆ alkyl substituted with optionally functionally modified hydroxy, C₁₋₄ alkoxy or halogens, a C₆₋₁₂ aryl or a 5- to 6-membered hetaryl radical which contains one to three N, O and/or S atoms, the aryl and hetaryl radical optionally being substituted with C₁₋₄ alkyl, C₁₋₄ alkoxy, hetaryl or CF₃, or R⁵ and R⁶ together mean a --(CH₂)_(n) -- group and R¹ and R mean hydroxy, C₁₋₆ alkoxy or NR¹⁰ R¹¹, R² means hydrogen, C₁₋₄ alkyl or C₁₋₄ alkoxy-C₁₋₂ alkyl, R⁹ means hydrogen or C₁₋₆ alkyl, n means 3 or 4, R⁷ or R⁸ each mean hydrogen, C₁₋₆ alkyl, acyl or phenyl which is optionally substituted singly or repeatedly with C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen or CF₃, R¹⁰ and R¹¹ each mean hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl or a C₆₋₁₂ aryl radical or a 5- to 6-membered hetaryl radical, which contains one to three N, O and/or S atoms, and the aryl and hetaryl radicals are optionally substituted singly or repeatedly with C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen or CF₃.
 2. A compound according to claim 1, in which A means ----N═CR⁵ --CR⁶ ═N----.
 3. A compound of claim 1, which is:isopropyl-11-ethyl-3-methyl-pyrazino-[2,3g]-β-carboline-10-carboxylate isopropyl-11-ethyl-2-methyl-pyrazino-[2,3-g]β-carboline-10-carboxylate isopropyl-11-methoxymethyl-2,3,4,5-tetrahydroquinoxalino-[2,3g]β-carboline-12-carboxylate, isopropyl-3,11-bis(methoxymethyl)-pyrazino-[2,3-g]β-carboline-10-carboxylate, 7H -benzo[e]pyrido[3,4-b]-indole-11-methoxymethyl-10-carboxylic acid-isopropyl ester, 10-methyl-2-propyl-oxazolo[4,5-g]-β-carboline-9-carboxylic acid isopropyl ester, 2-(1,2-dihydroxyethyl)-10-methoxymethyl-oxazolo-[4,5-g]-β-carboline-9-carboxylic acid isopropyl ester, 10-methoxymethyl-2-isopropyl-oxazolo-[4,5-g]-9-(5-methoxymethyl-3-isoxazolyl)-β-carboline, 2-amino-10-ethyl-thiazolo[4,5-g]-β-carboline-9-carboxylic acid isopropyl ester, 2-amino-10-methoxymethyl-thiazolo[4,5-g]-β-carboline-9-carboxylic acid isopropyl ester, pyrrolo[4,5-g]-β-carboline-2,5-dicarboxylic acid diethyl ester, 2-isopropyl-10-methoxymethyl-1H-imidazo[4,5-g]-β-carboline-9-carboxylic acid isopropyl ester or 10-ethyl-2-methyl-thiazolo[5,4-g]-β-carboline-9-carboxylic acid isopropyl ester.
 4. A process for the production of a compound according to claim 1, which comprises:a) reacting a compound of formula II ##STR17## with a 2-azadiene of formula III ##STR18## in which R³, R⁴ and A have the above meaning, and X and Y represent leaving groups, in the presence of acids or b) aromatizing a compound of formula IV ##STR19## in which R³, R⁴ and A have the above meaning, or c) reacting a compound of formula V ##STR20## in which R³ and R⁴ have the above meaning, with an α,β-unsaturated aldehyde to a fused pyridine or with a primary amine H₂ N--CH₂ --R⁵ to a fused imidazole or reacting the diazonium salts obtained with nitrites with acetoacetic acid derivatives to an ethylidenehydrazine derivative and cyclizing the latter to the pyrrole or reacting a thiocyanate or isothiocyanate derivative to a fused thiazole or d) reacting a compound of formula VI ##STR21## in which R³ and R⁴ have the above meaning, with a primary amine H₂ N--CH₂ --R⁵ to a fused oxazole or with a vicinal primary diamine ##STR22## to a fused pyrazine or e) cyclizing a nitrile oxide of formula VII ##STR23## with =--R² to an isoxazole derivative, f) reacting an α-haloketone of formula VIII ##STR24## in which R⁴ and A have the above meaning and Z is halogen, with a thioamide H₂ N--CS--R⁹ to a compound with R³ meaning thiazolyl or g) cyclizing a nitrile of formula IX ##STR25## in which R⁴ and A have the above meaning, with an azide to a compound with R³ meaning tetrazolyl,and optionally then saponifying or reesterifying an ester group, esterifying a carboxyl group, alkylating or acylating an amino group, releasing a functionally modified hydroxy group, separating the isomers or forming a physiologically compatible salt.
 5. A pharmaceutical composition which comprises a compound according to claim 1 or an isomer, tautomer or salt thereof, and at least one pharmaceutically acceptable vehicle and/or adjuvant.
 6. A method for treating a condition or disease which comprises administering to a patient a composition according to claim 5 sufficient to produce anxiolytic, anti-amnestic and/or nootropic activity.
 7. The method of claim 6, wherein the method is for improving learning or attentiveness.
 8. The method of claim 6, wherein the method is for treatment of geriatric symptoms.
 9. The method of claim 6, wherein the method is for mitigation of cognitive deficit and increase of vigilance.
 10. The method of claim 6, wherein the compound according to claim 1 or an isomer, tautomer or salt thereof is administered in a daily dose of 0.1 to 300 mg.
 11. A compound according to claim 1, which is the compound isopropyl-11-methoxymethyl-3-methyl-pyrazino[2,3-g]-β-carboline-10-carboxylate, isopropyl-11-ethyl-3-methyl-pyrazino[2,3-g]-β-carboline-10-carboxylate, or isopropyl-11 -ethyl-2-methyl-pyrazino[2, 3-g]-β-carboline-10-carboxylate.
 12. A compound of the formulae I, or an isomer, tautomer or salt thereof, according to claim 1, wherein A is a 5- or 6-membered unsaturated heterocycle ring having 1 or 2 N, O and/or S atoms in the ring and which is optionally substituted by R⁵ and R⁶.
 13. A compound of the formulae I, or an isomer, tautomer or salt thereof, according to claim 1, wherein A is a 6-membered unsaturated heterocycle ring having 1 or 2 N atoms in the ring and which is optionally substituted by R⁵ and R⁶.
 14. A compound of the formulae I, or an isomer, tautomer or salt thereof, according to claim 1, wherein R⁵ and R⁶ are the same or different and are hydrogen, C₁₋₆ alkyl or phenyl or R⁵ and R⁶ together are --(CH₂)₃₋₄ -.
 15. A compound of the formulae I, or an isomer, tautomer or salt thereof, according to claim 1, wherein R³ is --COR¹.
 16. A compound of the formulae I, or an isomer, tautomer or salt thereof, according to claim 1, wherein each aryl group, when present, is independently a phenyl, biphenyl or α- or β-naphthyl group.
 17. A compound of the formulae I, or an isomer, tautomer or salt thereof, according to claim 1, wherein each hetaryl group, when present, is independently a triazine, pyridine, pyrimidine, pyrazine, pyridazine, furan, thiophene, pyrrole, imidazole, thiazole, 1,2,4-oxadiazolyl or 1,3,4-oxadiazolyl.
 18. A compound of the formulae I, or an isomer, tautomer or salt thereof, according to claim 1, wherein each hetaryl group, when present, is independently a benzoyl of 1-6 carbon atom alkanoyl group.
 19. A compound of the formulae I, or an isomer, tautomer or salt thereof, according to claim 1, wherein each functionally modified hydroxy group, when present, is independently an etherified or esterified hydroxy group. 